Tumor evolution metrics predict recurrence beyond 10 years in locally advanced prostate cancer

Date

2024-01-01

Author

Fernandez-Mateos, Javier
Cresswell, George D.
Trahearn, Nicholas
Webb, Katharine
Sakr, Chirine
Lampis, Andrea
Stuttle, Christine
Corbishley, Catherine M.
Stavrinides, Vasilis
Zapata, Luis
Spiteri, Inmaculada
Heide, Timon
Gallagher, Lewis
James, Chela
Ramazzotti, Daniele
Gao, Annie
Kote-Jarai, Zsofia
Acar, Ahmet
Truelove, Lesley
Proszek, Paula
Murray, Julia
Reid, Alison
Wilkins, Anna
Hubank, Michael
Eeles, Ros
Dearnaley, David
Sottoriva, Andrea

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up. We concomitantly assessed morphological heterogeneity using deep learning in 1,923 histological sections from 250 individuals. Genetic and morphological (Gleason) diversity were independent predictors of recurrence (hazard ratio (HR) = 3.12 and 95% confidence interval (95% CI) = 1.34–7.3; HR = 2.24 and 95% CI = 1.28–3.92). Combined, they identified a group with half the median time to recurrence. Spatial segregation of clones was also an independent marker of recurrence (HR = 2.3 and 95% CI = 1.11–4.8). We identified copy number changes associated with Gleason grade and found that chromosome 6p loss correlated with reduced immune infiltration. Matched profiling of relapse, decades after diagnosis, confirmed that genomic instability is a driving force in prostate cancer progression. This study shows that combining genomics with artificial intelligence-aided histopathology leads to the identification of clinical biomarkers of evolution.

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https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85198495554&origin=inward
https://hdl.handle.net/11511/110217

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Department of Biology, Article